Survival outcomes in patients with relapsed/refractory or MRD-positive B-cell acute lymphoblastic leukemia treated with blinatumomab

Blinatumomab has demonstrated significant efficacy in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-cell ALL) and patients with measurable residual disease (MRD). This review aimed to compare median relapse-free survival (RFS) and median overall survival (OS) in adult and pediatric patients with R/R or MRD-positive B-cell ALL from pivotal studies [MT-103-211 and TOWER for adults with Philadelphia chromosome (Ph)-negative R/R B-cell ALL, ALCANTARA for adults with Ph-positive R/R B-cell ALL, MT-103-203 for adults with MRD-positive B-cell ALL, and MT-103-205 for pediatric patients with R/R B-cell ALL], with the median RFS and OS from retrospective analyses, country or ethnicity-specific studies, and studies based on real-world evidence (RWE) identified from a literature search. Adults with Ph-negative R/R B-cell ALL who received blinatumomab as first salvage demonstrated a numerically longer median OS compared with that in patients from pivotal studies (MT-103-211 and TOWER) without additional safety concerns. In pediatric patients with R/R B-cell ALL treated with blinatumomab, the median RFS and OS from retrospective analyses and country/ethnicity-specific studies were comparable with the median RFS and OS from the pivotal study MT-103-205. The median RFS and OS from RWE studies in adults with R/R B-cell ALL were numerically longer than the median RFS and OS from pivotal studies (MT-103-211, TOWER, and ALCANTARA); however, this trend was not observed in pediatric patients with R/R B-cell ALL. In conclusion, this analysis identified first salvage adults with Ph-negative R/R B-cell ALL as particularly well-suited for treatment with blinatumomab since survival outcomes from retrospective analyses reported in this patient subgroup were numerically better compared with those from pivotal studies without additional safety signals.


Introduction
B-cell acute lymphoblastic leukemia (B-cell ALL) is caused by the malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. 1 Despite improvements in treatment outcomes recorded in patients with newly diagnosed B-cell ALL, disease relapse remains the main cause of treatment failure.3][4][5][6][7][8][9] Survival rates are worse in patients with second or later relapse.Historically, Volume 14 2 journals.sagepub.com/home/tah TherapeuTic advances in hematology treatment options for patients with relapsed/ refractory (R/R) B-cell ALL have been limited to conventional chemotherapy, followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) in eligible patients.Due to the poor outcomes observed with chemotherapy, novel and more effective treatment options are needed.
Blinatumomab is a novel immunotherapy based on the BiTE® (bispecific T-cell engager) immuno-oncology platform that redirects CD3positive T cells to serially engage and lyse CD19expressing B cells, including leukemic blasts. 10,11ased on its tolerable safety profile and a high response rate, blinatumomab was first approved by the US Food and Drug Administration (FDA) for the treatment of R/R B-cell ALL in adults and pediatric patients and later for B-cell ALL with measurable residual disease (MRD; defined as the presence of ⩾10 −3 leukemic blasts). 12ubsequently, blinatumomab was approved by the European Medicines Agency for the same indications. 13Since its approval, a large number of patients with R/R and MRD-positive B-cell ALL have been treated with blinatumomab.In addition to the results obtained from pivotal studies (defined as studies based on which the FDA approval was granted), data on survival in specific patient subgroups have been gathered in retrospective analyses, ethnicity/country-specific studies, and studies based on real-world evidence (RWE).Comparison of survival outcomes from these studies with those from pivotal studies may provide insight into patient subgroups that may benefit preferentially from blinatumomab.The objective of this review was to compare the survival outcomes -relapse-free survival (RFS) and overall survival (OS) -from the pivotal studies with those from retrospective analyses, single country-or ethnicity-specific studies, and RWEbased studies in patients with R/R B-cell ALL or patients with B-cell ALL with MRD treated with blinatumomab.

Methods
A PubMed search was performed using a search string with the following Boolean operators: 'Blinatumomab AND [(ALL) OR (acute AND lymphoblastic AND leukemia)] AND [(duration of response) OR (DoR) OR (time to hematologic relapse) OR (duration of overall response) OR (duration of remission) OR (durability of response) OR (event-free survival) OR (EFS) OR (relapse-free survival) OR (RFS) OR (overall survival) OR (OS)]'.The search identified 257 publications as of December 2022, of which 38 articles were found to report data for pivotal studies, retrospective analyses, ethnicity/country-specific studies, or RWE-based studies on median RFS or median OS in adult or pediatric patients with R/R B-cell ALL or MRD-positive B-cell ALL treated with blinatumomab (Figure 1).In addition, nine abstracts/posters presented at annual meetings of the American Society of Hematology (ASH), European Hematology Association (EHA), or American Society of Clinical Oncology (ASCO) based on studies sponsored by Amgen and those sponsored by institutions independent of Amgen were included.Articles published in the past 10 years (2013-2022) and abstracts published in the past 5 years (2018-2022) were considered.Reviews or metaanalyses were not included.Relevant articles and abstracts were grouped based on the type of patients assessed.Patients were subsequently grouped based on age, R/R disease with/without the presence of the Philadelphia chromosome (Ph), and the presence of MRD following frontline chemotherapy.

Adults with R/R Ph-negative B-cell ALL
Pivotal studies MT-103-211 was a multicenter, single-arm, open-label phase II study that enrolled 189 patients [median age, 39 years (range, 18-79)] with R/R Ph-negative B-cell ALL 14 who received blinatumomab by continuous intravenous (cIV) infusion at a target dose of 9 µg/day in the first week, followed by 28 µg/day for the remaining 3 weeks, repeated in 6-week cycles for up to five cycles.This study included patients with early relapse (defined as those in whom the relapse occurred within 12 months of the first remission or 12 months after receiving alloHSCT) or patients who did not respond to or relapsed after salvage therapy.After the first two cycles, 43% of the patients achieved complete remission (CR)/ complete remission with partial hematological response (CRh).In patients who achieved CR/ CRh, the median RFS was 5.9 months [95% confidence interval (CI), 4.8-8.3]and the median OS in patients treated with blinatumomab was 6.1 months (95% CI, 4.2-7.5).

TherapeuTic advances in hematology
the median OS for patients treated with blinatumomab was 7.6 months (Amgen data on file), which was similar to the median OS reported in the primary study. 15

Key retrospective analyses based on prospective clinical studies
Retrospective analyses of results from clinical studies have provided further insight into the RFS and OS in specific patient subgroups.A retrospective analysis by Stein et al. 16 assessed data from 64 adult patients with R/R Ph-negative B-cell ALL with prior relapse following alloHSCT before enrollment in the above-mentioned phase II study (MT-103-211).Among patients receiving blinatumomab, 45.0% achieved CR/CRh within the first two treatment cycles; in these patients, the median RFS was 7.4 months (95% CI, 5.0-10.1)after a median follow-up of 12.4 months (Table 1 and Supplemental Figure 1).e Continuous hematologic CR.CR is defined as ⩽5% bone marrow and no evidence of disease, platelet count >100,000 per µL, and absolute neutrophil count >1000 per µL.CRh is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count >50,000 per µL, and absolute neutrophil count >500 per µL.CRi is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count of >100,000 per µL or absolute neutrophil count of >1000 per µL.AE, adverse event; ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR, complete remission with full hematologic recovery; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRS, cytokine release syndrome; HSCT, hematologic stem cell transplantation; MRD, measurable residual disease; NA, not applicable; NE, not estimable; NR, not reached; OS, overall survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; R/R, relapsed / refractory.AlloHSCT following the achievement of CR has been suggested as a potentially curative approach for patients with R/R B-cell ALL.Jabbour et al. performed a retrospective analysis 25 to assess the effect of alloHSCT on survival in patients treated with blinatumomab in the phase III TOWER study.Of the 97 patients who underwent onstudy alloHSCT, 65 received prior treatment with blinatumomab, of whom 77.0% had CR/ CRh/CRi.With a median follow-up of 7.2 months, the median RFS in patients who achieved CR/ CRh/CRi in response to treatment with blinatumomab followed by subsequent on-study alloHSCT was 8.8 months (95% CI, 5.5-12.1)compared with a median RFS of 6.7 months (95% CI, 5.3-8.1) in patients treated with blinatumomab without subsequent on-study alloHSCT (p = 0.97).The median OS was not reached in patients with CR/CRh/CRi who received subsequent alloHSCT compared with 16.0 months for those with CR/CRh/CRi but no alloHSCT (OR, 1.17; 95% CI, 0.5-2.5;p = 0.69).There was insufficient evidence to detect a difference in the survival outcomes between patients who did or did not receive on-study alloHSCT following treatment with blinatumomab.Survival was found to be dependent on response to treatment with blinatumomab regardless of whether patients had on-study alloHSCT.

Key country-specific or ethnicity-specific studies
Prospective studies aimed at demonstrating the efficacy of blinatumomab in patients with R/R B-cell ALL from a specific country or a specific ethnic background have been conducted.A multicenter, single-arm study that enrolled 90 heavily pretreated patients with R/R Ph-negative B-cell ALL from China showed that at a dosing similar to that followed in the pivotal studies (MT-103-211 and TOWER), the rate of CR/CRh within two cycles of blinatumomab was 45.6% (95% CI, 35.0-56.4). 30,31The median RFS in patients with journals.sagepub.com/home/tahTherapeuTic advances in hematology CR/CRh was 4.3 months (95% CI, 3.2-9.4),and the median OS in all patients treated with blinatumomab was 9.2 months (95% CI, 6.5-11.7).A phase Ib/II study conducted in Japan in patients with R/R Ph-negative B-cell ALL showed that 8 of 21 patients (38.0%) in the phase II part of the study achieved CR/CRh within two cycles of blinatumomab treatment.The median RFS among these patients was 5.0 months (95% CI, 3.5-6.4)and the median OS was NE (95% CI, 7.4-NE). 33nother study that evaluated the safety and efficacy of blinatumomab in Korean patients with R/R Ph-negative B-cell ALL showed that 22 of the 49 evaluable patients (44.9%) achieved CR/ CRh. 32The median RFS in patients with CR/ CRh was 7.5 months, which was significantly longer than the median RFS of 2.0 months in patients who did not achieve CR/CRh (p < 0.001).The median OS was significantly longer in patients with CR/CRh compared with those without CR/CRh (8.1 versus 5.2 months, p < 0.001).A similar trend was seen in patients who underwent alloHSCT after treatment with blinatumomab; these patients had a median RFS of 7.5 versus 2.4 months in patients with no alloHSCT (p < 0.001) and the median OS was 7.5 versus 5.2 months (p = 0.058).A retrospective analysis of 45 Asian patients with R/R Ph-negative B-cell ALL pooled from two studies -TOWER 15 and the phase Ib/II study in Japanese patients reported by Kiyoi et al. 33 -showed that the median RFS in patients who achieved CR/CRh in response to blinatumomab within the first 12 weeks was 8.9 months (95% CI, 3.8-10.7)and the median OS was 11.9 months (95% CI, 9.9-17.1). 34verall, the median RFS and median OS in Asian patients with R/R Ph-negative B-cell ALL were comparable to the median RFS and median OS reported in pivotal clinical studies (MT-103-211 and TOWER).

Pivotal study
The presence of the Ph is associated with poor outcomes in patients with R/R B-cell ALL. 35The open-label, multicenter, single-arm, phase II study -ALCANTARA -enrolled 45 adult patients with R/R Ph-positive B-cell ALL who had either progressed or not responded to second-or later-generation tyrosine kinase inhibitors (TKIs) or those who were intolerant to TKI therapy (Table 2 and Supplemental Figure 2). 36A total of 16 patients (35.6%) achieved CR/CRh within the first two cycles; of these, 88.0% had a complete MRD-negative response (defined as no detectable polymerase chain reaction amplification of BCR-ABL1 genes at a sensitivity ⩾10 −5 ).With a median follow-up of 9.0 months, the median RFS was 6.7 months (95% CI, 4.4-NE) and the median OS was 7.1 months (95% CI, 5.6-NE).None of the patients experienced grade ⩾ 3 CRS and the incidence of grade ⩾ 3 neurologic AEs was 6.7%.The long-term followup study of the 45 patients enrolled in the primary study showed that the median RFS was 6.8 months (95% CI, 4.4-NE) at a median follow-up of 16.1 months and the median OS was 9.0 months (95% CI, 5.7-13.5)at a median follow-up of 25.1 months. 37The median OS in patients with CR [19.8 months (95% CI, 12.1-NE)] was longer than in those without CR [6.0 months (95% CI, 2.9-7.1)].

Retrospective analyses or country-specific/ ethnicity-specific studies
No retrospective analyses aimed at the assessment of RFS and OS in specific patient subgroups from within the pivotal ALCANTARA study or other country/ethnicity-specific studies in patients with R/R Ph-positive B-cell ALL have been reported.

Adult patients with MRD-positive B-cell ALL
Pivotal study A phase II study -BLAST (MT-103-203) -evaluated the efficacy and tolerability of blinatumomab in patients with MRD-positive B-cell ALL with first or later CR at baseline. 38MRD positivity was defined as the presence of ⩾10 −3 leukemic blasts.Patients found to be MRD positive after receiving a minimum of three blocks of intensive chemotherapy were eligible to receive treatment with blinatumomab.Blinatumomab was administered as cIV infusion at a dose of 15 µg/m 2 /day over 4 weeks, followed by a treatment-free period of 2 weeks, which was defined as one 6-week treatment cycle.Patients with Ph-positive B-cell ALL were excluded from the survival analysis.Of the 113 evaluable patients, 88 (77.9%) had a complete MRD response (defined as no detectable leukemic blasts) at the end of cycle 1 of blinatumomab; two additional patients showed an MRD response following

TherapeuTic advances in hematology
blinatumomab.The median RFS in patients with R/R B-cell ALL (Ph negative, n = 172; Ph positive, n = 55) was 32.1 months (95% CI, 9.5-NR), which was numerically about five times longer than the median RFS reported in the pivotal MT-103-211 study by Topp et al. 14 (5.9 months; median RFS was not reported for TOWER).In the subgroup of patients who were Ph positive and treated with blinatumomab alone (n = 32), the median RFS was 32.0 months, which was also numerically about four times longer than the median RFS reported in the final analysis for ALCANTARA (6.8 months).With a median follow-up of 14.0 months, the median OS in patients with R/R (Ph negative, n = 172; Ph positive, n = 55) B-cell ALL treated with blinatumomab was 12.7 months (95% CI, 9.2-17.9),which was about twice the median OS reported for patients with R/R Ph-negative B-cell ALL from the pivotal studies -phase II study by Topp et al. (6.1 months) and TOWER (7.7 months).Among patients with R/R Ph-positive B-cell ALL who received blinatumomab alone, the median OS was 13.1 months, which was numerically longer than the median OS reported among patients from the final analysis for ALCANTARA (9.0 months).
Results from another large observational study (NEUF), where patients were enrolled in the expanded access program in selected European countries -France, Italy, Russia, Spain, and the UK -were based on the analysis of RWE from 106 patients with R/R Ph-negative B-cell ALL.In patients who achieved CR/CRh/CRi, the median RFS was 11.0 months (range, 0.0-15.4). 41The median OS was 12.2 months (range, 0. upon a median follow-up of 13.0 months. 45verall, the median RFS and median OS assessed in patients with R/R B-cell ALL from studies based on analysis of real-world data were numerically longer compared with those reported in the pivotal studies.

Patients with MRD-positive B-cell ALL
In the retrospective analysis of RWE by Badar et al. discussed earlier, 12 patients received blinatumomab for MRD-positive B-cell ALL and 8 (75.0%) were MRD negative after treatment. 40he median RFS for patients who received blinatumomab for MRD-positive B-cell was NR (54.0% of patients were MRD negative at the end of 2-year follow-up) and the median OS was 34.7 months (95% CI, 8.8-34.7;median followup, 6.0 months), which was similar to the median OS reported for patients from the pivotal BLAST study (38.9 months).Another report based on an analysis of real-world data from 109 patients with MRD-positive B-cell ALL enrolled in the NEUF study showed a median RFS of 27.6 months, which was comparable with the median RFS reported in the pivotal BLAST study (23.6 months), 38 while the median OS was NR. 46 Thus, the median RFS and median OS in patients with MRD-positive B-cell ALL treated with blinatumomab reported in studies based on RWE were comparable with the median RFS and median OS reported in BLAST.

Pediatric patients with R/R or MRD-positive B-cell ALL
Treatment of R/R B-cell ALL in pediatric patients has remained a challenge, with survival rates lower than those observed at initial diagnosis.An initial study by Handgretinger et al. in three pediatric patients with post-transplant relapsed B-cell ALL showed that these patients achieved a CR when treated with blinatumomab in addition to infusion with donor T cells. 47Another follow-up report showed that of the nine patients treated with blinatumomab for post-HSCT relapse, six achieved CR. 48votal study An open-label, multicenter, single-arm, phase I/II study, MT-103-205, was conducted in pediatric patients with R/R B-cell ALL to assess the optimal dosage, safety, and efficacy of blinatumomab. 49Eligible patients were <18 years of age (2-17 years of age in the dose-escalation phase) with B-cell ALL with >25% bone marrow blasts who were in second or later relapse or ).The incidence of grade ⩾ 3 neurologic AEs was 4.0% and the incidence of grade ⩾ 3 CRS was 6.0%.
A long-term follow-up analysis assessed survival in 70 patients treated with the recommended phase II dose over 24 months from the start of blinatumomab. 53The median OS was 7.5 months (95% CI, 4.0-11.8).Prior alloHSCT was associated with prolonged survival after treatment with blinatumomab; the median OS was 10.6 months (95% CI, 4.2-17.3)for patients who had previously received alloHSCT versus 4.3 months (95% CI, 2.9-10.4)for those who had not (p = 0.1414).A total of 25 of 70 patients received alloHSCT following treatment with blinatumomab.OS appeared to be longer in patients who received alloHSCT as compared with those who did not.Thus, alloHSCT before or after treatment with blinatumomab improved the probability of OS.
Patients with a complete MRD response (no target amplification with a minimum sensitivity of 10 −4 ) had a median OS of 14.6 months compared with a median OS of 5.7 months in patients without a complete MRD response; this finding is similar to the trend seen in adult patients.

Clinical study supportive of the pivotal study
Locatelli et al. reported results of an open-label, single-arm, expanded access international study in pediatric patients with CD19-positive R/R B-cell ALL (⩾5% blasts) or MRD-positive (<5% blasts but with MRD level ⩾10 −3 ) B-cell ALL -RIALTO. 50Blinatumomab was administered at a dose of 5-15 µg/m 2 per day as a 6-week induction cycle which comprised of cIV for 4 weeks, followed by a 2-week treatment-free period for a maximum of two induction cycles.Patients who achieved CR were eligible for three additional consolidation cycles.Of the 110 patients enrolled, 98 had R/R disease and 12 were MRD positive (⩽5% blasts at baseline).Of the 98 patients with R/R disease, 58 (   49 likely due to the enrollment of a higher number of patients with a lower tumor burden (<50% blasts) in RIALTO.
The effect of treatment with blinatumomab in pediatric patients with first-relapse B-cell ALL was investigated in two recent randomized phase III studies.In the first study, Brown et al. investigated the effects of blinatumomab versus chemotherapy when administered as consolidation therapy post-reinduction in children and young adults with first-relapse B-cell ALL. 51All patients received 4 weeks of reinduction chemotherapy followed by randomization to receive either two cycles of blinatumomab or two cycles of chemotherapy followed by alloHSCT.Of the 208 patients who were randomized, 118 (57%) received treatment with blinatumomab or chemotherapy.Randomization was terminated at the recommendation of the data and safety monitoring committee without compliance with the rules for termination due to concerns regarding clinical equipoise between the randomized treatments.With a median follow-up of 2.9 years, the 2-year estimate of disease-free survival was 54.4% for patients in the blinatumomab group versus 39.0% for those in the chemotherapy group [HR for disease progression or mortality, 0.07 (95% CI, 0.47-1.03);one-sided p = 0.03].Among patients who received the randomized therapy, the Polish pediatric patients with R/R B-cell ALL. 60 In all, 11 of the 13 patients received alloHSCT after treatment with blinatumomab, all of whom were alive without relapse with a follow-up of 25.4 months.These results support the idea that alloHSCT following treatment with blinatumomab could prolong survival in pediatric R/R B-cell ALL.

Discussion
Results from pivotal studies, retrospective analyses based on clinical studies, studies in patients from specific countries and/or ethnicities, and the analysis of RWE have provided an opportunity to compare survival outcomes in specific subgroups of patients treated with blinatumomab.A key finding of this literature review was that, although treatment with blinatumomab was beneficial as both first and later salvage, the effects of treatment were more favorable when blinatumomab was administered as the first salvage therapy and in patients with molecularly resistant disease compared with those treated for overt recurrence, especially if associated with a bone marrow blast infiltration of greater than 50.0%. 6322,23 In addition, the safety profile for patients who received blinatumomab as first salvage was generally similar to the safety profile for all patients from the MT-103-211 and TOWER studies. 14,15tients who achieved a complete MRD response after treatment with blinatumomab had better RFS and OS compared with patients who did not achieve a CR or MRD response.The median RFS and median OS in patients with R/R Ph-negative B-cell ALL who achieved CR/CRh and a complete MRD response after blinatumomab therapy were numerically longer compared with the median RFS and median OS reported in patients from the pivotal MT-103-211 and TOWER studies without the incidence of additional AEs. 15,17,26Analysis of journals.sagepub.com/home/tah TherapeuTic advances in hematology long-term outcomes in MRD-positive patients who achieved a complete MRD response after treatment with blinatumomab found a 5-year survival rate of 50.0%regardless of the status of alloHSCT. 39atients with B-cell ALL who are MRD positive before alloHSCT have a significantly higher rate of relapse and lower OS compared with patients who are MRD negative. 64,65Thus, patients who are MRD positive before alloHSCT could be considered for treatment with blinatumomab maintenance after transplantation.In this regard, Gaballa et al. recently reported on the feasibility of four cycles of blinatumomab administered every 3 months during the first year after transplantation to prevent relapse in high-risk B-cell ALL patients. 66he median time from transplantation to the first cycle of blinatumomab was 78 days (range, 44-105).The treatment was well tolerated, and no relevant toxicity was recorded.Additional studies are needed to document if this approach can be of benefit for disease eradication.
The goal of therapy in R/R B-cell ALL is to induce CR followed by consolidation of CR with alloHSCT in most adult and selected pediatric patients.The role of alloHSCT in the extension of survival in patients who respond to blinatumomab versus those who do not respond to blinatumomab is not yet fully understood, which is due, in part, to the fact that neither are the indications for alloHSCT defined in prospective trials nor is alloHSCT a standardized procedure, with much heterogeneity in the use of conditioning regimens, donor selection, and management of post-transplant immune suppression across the large number of centers.This creates room for hard-to-characterize biases and makes conclusions difficult.A retrospective analysis in adults with R/R B-cell ALL showed that survival outcomes were dependent on response to treatment with blinatumomab irrespective of whether patients received alloHSCT following blinatumomab. 25By contrast, an analysis of long-term survival of patients from two clinical studies showed that treatment with blinatumomab followed by alloHSCT improved median OS. 20 Additional studies designed to prospectively assess the effect of blinatumomab followed by alloHSCT in adults with R/R B-cell ALL are therefore needed.In the case of pediatric patients with R/R B-cell ALL, Queudeville et al. 56 demonstrated a positive effect of blinatumomab followed by alloHSCT on OS and the recent RIALTO trial 50 showed a trend toward better RFS and OS in patients treated with blinatumomab followed by alloHSCT. 50,56Results of the recently published randomized phase III study by Locatelli et al., 52,55 where alloHSCT was prospectively indicated in patients with high-risk first-relapse B-cell ALL following a third consolidation course with one cycle of blinatumomab, demonstrated a significant improvement in EFS and OS than in patients treated with chemotherapy.
Recent years have witnessed the introduction of other forms of immunotherapy in patients with B-cell ALL, including the anti-CD22 antibodydrug conjugate inotuzumab ozogamicin (InO) and anti-CD19 chimeric antigen receptor T-cell therapy (CART-19), which have shown significant efficacy in patients with R/R B-cell ALL. 67,68Results from different trials using blinatumomab, InO, or CART-19 are often compared; however, a better approach could be to design a strategy for the use of these agents in combination and/or sequentially with the intent to improve long-term survival.A recent case study demonstrated positive results in patients with Ph-positive R/R B-cell ALL who were treated sequentially with InO and blinatumomab. 69he IntReALL 2020 study protocol will test the sequential use of both InO and blinatumomab in children with the first relapse of B-cell ALL (Locatelli F, personal communication).Patients with prior exposure to blinatumomab have been demonstrated to respond to subsequent treatment with CART-19.In the pivotal phase I/II ZUMA-3 study, the rate of CR/CRi among patients with R/R B-cell ALL treated with CART-19 with prior exposure to blinatumomab in any line (12 of 21 patients; 57%) was similar to the rate of CR/CRi observed in the overall patient population treated with CART-19 (31 of 45 patients; 69%). 70Another report based on a retrospective multicenter analysis of 420 patients aged ⩽25 years who were treated with CART-19 demonstrated that although prior exposure to blinatumomab led to downregulation of CD19 expression, it did not preclude a response to salvage therapy with CART-19. 71Poor response to prior treatment with blinatumomab, rather than prior exposure to blinatumomab, was predictive of poor outcome to subsequent therapy with CART-19.This finding suggests that an intrinsic T-cell dysfunction is more relevant to predict the probability of response to CART-19 than prior exposure to a CD19-directed treatment.
We found that the median RFS and median OS reported in studies based on RWE in adult patients with R/R B-cell ALL treated with blinatumomab were longer compared with the median RFS and median OS reported in pivotal studies (MT-103-211, TOWER, and ALCANTARA).A possible explanation could be the enrollment of a greater number of heavily pretreated patients and patients with relapse after alloHSCT in the pivotal studies.
Novel treatment strategies could further improve survival outcomes in patients with R/R or MRDpositive B-cell ALL.The combination of blinatumomab with InO or other targeted therapies followed by alloHSCT and subsequent monitoring of MRD could help improve survival outcomes.A subcutaneous formulation of blinatumomab that allows for greater systemic exposure to blinatumomab compared with the dose used for intravenous administration is currently being evaluated and has demonstrated promising early signals.

Conclusion
This review of the published literature demonstrated the consistency of the efficacy and safety of blinatumomab for the treatment of R/R B-cell ALL from pivotal studies as well as studies based on retrospective analyses and RWE.The results were consistently superior when blinatumomab was given in the first salvage compared with later salvages.While the comparative results of blinatumomab, InO, and CART-19 may be of interest, we believe such questions are not as critical as investigating the efficacy and safety of the combinations of these therapies -blinatumomab and InO and its combination with standard chemotherapy -and the value of CART-19 or alloHSCT after induction of CR and/or MRD-negative status.This should be the focus of our current and future studies in ALL.

Figure 1 .
Figure 1.Flow chart for the strategy used for the literature search.

Table 1 .
Median RFS and median OS in adult patients with R/R Ph-negative B-cell ALL treated with blinatumomab from pivotal studies, retrospective analyses, and single country or ethnicity-specific studies.

Table 1 .
23ontinued)The median DoR was 10.7 months (95% CI, 5.6-NE) compared with 6.2 months (95% CI, 3.8-9.6) in patients treated with blinatumomab as first or second/later salvage therapy, respectively.The incidence of grade 3 AEs of interest reported in at least 3% of patients (61.2% versus 67.7%), grade 3 neurologic AEs (7.8% versus 9.1%), and grade 3 CRS (3.9% versus 4.9%) were comparable in patients who received blinatumomab as first versus second/later salvage.In the second retrospective analysis by Topp et al.,23data from two phase II studies and the phase III TOWER study were analyzed.Patients who received blinatumomab as first salvage com- 22.4 months (95% CI, 2.3-24.9) in patients who achieved CR/CRh and one previous relapse and 6.2 months [95% CI, 3.8-not estimable (NE)] in patients who had two or more previous relapses.Similar to the trend seen with RFS, the median OS was approximately twice as long for patients with one previous relapse compared with patients with two or more previous relapses[14.3months(95%CI,4.0-23.1)versus6.5 months (95% CI, 3.5-9.3)].In two other retrospective analyses, patients with R/R B-cell ALL treated with blinatumomab were assessed for survival outcomes based on the status of first versus later relapse.In the first report by Dombret et al., which analyzed data from 104 and 167 adult patients treated with blinatumomab as first or second/later salvage therapy, respectively, from the phase III TOWER study, the median OS was numerically longer in patients treated in first salvage[11.1 months (95% CI, 8.2-not reached (NR))] compared with those receiving blinatumomab as second/ later salvage therapy [5.1 months (95% CI, 3.2-7.1)].22Asimilar trend was noted with the DoR in patients who achieved CR/CRh/CRi in response to blinatumomab.pared with second/later salvage therapy demonstrated higher rates of CR/CRh after two cycles [54.0%versus 41.0%; odds ratio (OR), 0.59; p = 0.005] and had a longer median OS [10.4 versus 5.7 months; hazard ratio (HR), 1.58; p < 0.001].The median RFS in patients who received blinatumomab as first salvage compared with second/later salvage therapy was numerically longer (10.1 versus 7.3 months; HR, 1.38; p = 0.061), the difference was not statistically significant.The safety profile of blinatumomab was generally similar between the two treatment groups (grade ⩾ 3 neurologic AEs, 13.0% versus 15.0%; grade ⩾ 3 CRS, 28.0% versus 38.0%; the latter event slightly greater in the blinatumomab as second/later salvage therapy group).These results indicate that although treatment with blinatumomab was beneficial when administered as either first or second/later salvage therapy, the effect of treatment was more favorable when blinatumomab was administered as first salvage therapy.

Table 2 .
Median RFS and median OS in adult patients with R/R Ph-positive B-cell ALL treated with blinatumomab from pivotal studies.
a Median RFS was calculated in patients with CR/CRh.CR is defined as ⩽5% bone marrow and no evidence of disease, platelet count >100,000 per µL, and absolute neutrophil count >1000 per µL.CRh is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count of >50,000 per µL, and absolute neutrophil count of >500 per µL.b Complete MRD response was defined as no detectable PCR amplification of BCR-ABL1 genes (sensitivity ⩾10 −5 ) as assessed by a central laboratory.AE, adverse event; ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR, complete remission with full hematologic recovery; CRh, complete remission with partial hematologic recovery; CRS, cytokine release syndrome; MRD, measurable residual disease; NE, not estimable; OS, overall survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; R/R, relapsed / refractory.Retrospective analyses or country-specific/ ethnicity-specific studiesNo retrospective analyses aimed at the assessment of RFS and OS in specific patient subgroups from the pivotal BLAST study or other Volume 14 10 journals.sagepub.com/home/tah

Table 3 .
Median RFS and median OS in adult patients with MRD-positive B-cell ALL treated with blinatumomab from pivotal studies.Complete MRD response was defined as no target amplification with a minimum sensitivity of 10 −4 .AE, adverse event; ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR, complete remission with full hematologic recovery; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRS, cytokine release syndrome; MRD, measurable residual disease; NE, not estimated; NR, not reached; OS, overall survival; RFS, relapse-free survival.
a MRD response was defined as either a complete MRD response or the presence of ⩽10 −4 detectable leukemic blasts.bMedianRFS was calculated in patients with CR/CRh/CRi and an MRD response at cycle 1 of blinatumomab.CR is defined as ⩽5% bone marrow and no evidence of disease, platelet count >100,000 per µL, and absolute neutrophil count >1000 per µL.CRh is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count >50,000 per µL, and absolute neutrophil count >500 per µL.CRi is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count of >100,000 per µL or absolute neutrophil count of >1000 per µL.cKey studies based on RWE in adult patientsPatients with R/R B-cell ALL Reports based on an analysis of RWE have provided further support to the efficacy of

Table 4 .
Median RFS and median OS from real-world evidence studies in adults with R/R or MRD-positive B-cell ALL treated with blinatumomab.Median RFS was calculated in patients with CR/CRh/CRi.CR is defined as ⩽5% bone marrow and no evidence of disease, platelet count >100,000 per µL, and absolute neutrophil count >1000 per µL.⩽5% bone marrow blasts and no evidence of disease, platelet count >50,000 per µL, and absolute neutrophil count >500 per µL.CRi is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count of >100,000 per µL or absolute neutrophil count of >1000 per µL.
a b Patients with CR/CRh/CRi.c Patients with CR. d Patients with CR/CRi.e NE, not estimable; NR, not reached; OS, overall survival; Ph, Philadelphia chromosome; RFS, relapse-free survival; R/R, relapsed/refractory; TKI, tyrosine kinase inhibitor.

Table 5 .
Median RFS and median OS in pediatric patients with R/R or MRD-positive B-cell ALL treated with blinatumomab from pivotal studies and retrospective analyses.

Table 6 .
Median RFS and median OS from real-world evidence studies in pediatric patients with R/R or MRD-positive B-cell ALL.
a Median RFS was calculated in patients with CR/CRh/CRi or MRD responders.bPatients with CR/CRh/CRi.CR is defined as ⩽5% bone marrow and no evidence of disease, platelet count >100,000 per µL, and absolute neutrophil count >1000 per µL.CRh is defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count >50,000 per µL, and absolute neutrophil count >500 per µL.CRi is defined as CRh was defined as ⩽5% bone marrow blasts and no evidence of disease, platelet count of >100,000 per microliter or absolute neutrophil count of >1000 per microliter.cInpatients with R/R or MRD-positive disease prior to treatment with blinatumomab.d MRD-positive was defined as ⩾10 −3 detectable blasts.e MRD response was defined as <10 −4 detectable blasts or ⩾2-log reduction of MRD value before and after blinatumomab administration.AE, adverse event; ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CI, confidence interval; CR, complete remission with full hematologic recovery; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recovery; CRS, cytokine release syndrome; IQR, interquartile range; MRD, measurable residual disease; NE, not estimable; NR, not reached; OS, overall survival; Ph, Philadelphia chromosome; R/R, relapsed/refractory; RFS, relapse-free survival.

Table 6 .
(Continued) Ethics approval and consent to participateNot applicable.journals.sagepub.com/home/tahTherapeuTic advances in hematology and CatalYm; in addition, RB has a patent for blinatumomab with royalties paid.GZ is an employee of, has patents from, and owns stock in Amgen Inc. FL has received personal fees from Amgen, personal fees from Novartis, other from Bellicum Pharmaceutical, other from Neovii, personal fees from Miltenyi, personal fees from Medac, personal fees from Jazz Pharmaceutical, and personal fees from Takeda, outside the submitted work.efficacy and safety of blinatumomab in adult patients with relapsed refractory B-precursor acute lymphoblastic leukemia.Blood 2018; 132: 4017-4017.19.Topp M, Stein AS, Zugmaier G, et al.Longterm survival of adults with B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) after treatment with blinatumomab and subsequent allogeneic hematopoietic stem cell transplantation (HSCT).J Clin Oncol 2018; 36: 7044-7044.20.Topp MS, Gökbuget N, Zugmaier G, et al.Long-term survival of patients with relapsed/ refractory acute lymphoblastic leukemia treated with blinatumomab.Cancer 2021; 127: 554-559.